The FDA recommends the submission of a plan of everything medical products for which an IND submission is required or for which clinical studies are intended to support a marketing submission under section 351(a) of the PHSA, or under 505(b)(1) ) or 505(b)(2) of the Federal Food, Drug and Cosmetic Act for an NDA. A plan is also recommended for medical products for which an IDE is required or for which clinical studies are intended to support a device marketing application (i.e. a 510 premarket notification( k), a PMA request, a De Novo classification request HDE request).
The FDA recommendations come at a time when several bills focusing on clinical trial diversity have recently been introduced in Congress. Although the proposed bills take a variety of approaches, at least one pending bill directs the FDA to issue regulations requiring sponsors to submit diversity plans to the agency and mandate post-approval monitoring to sponsors who fail to meet various enrollment goals. By issuing these draft guidelines, the FDA has set out an ambitious framework in the absence of legislative action or the development of notice-and-comment rules that aims to spur clinical trial sponsors to take more intentional action. to achieve research diversity in their studies.
The draft guidelines build on the November 2020 final guidelines, “Improving the diversity of clinical trial populations: Eligibility criteria, enrollment practices, and trial designs,” and the October 2016 final guidelines , “Collecting Race and Ethnicity Data in Clinical Trials”. In these previous documents, the FDA provided recommendations to sponsors on strategies to increase recruitment of underrepresented racial and ethnic populations, collect and report race and ethnicity data to the agency, and to develop and submit a plan to address the inclusion of clinically relevant populations for discussion with the agency.
The FDA cites inequities in access to health care, racism, and historical distrust of the clinical research system as reasons for the absence of underrepresented racial and ethnic populations in clinical research. Notably, the FDA also points out that the “increasing reliance” on small studies, intermediate endpoints, and other methods to expedite medical product approval underscores “the importance of prospectively defining the generation approach of data for a larger and more diverse population at the start of the development program. .”
The draft guidelines outline the content of five recommended elements for inclusion in the plan:
Scope of the medical product development program. Sponsors should describe the trials planned for the program. This section of the plan would include an outline of the proposed studies and how the inclusion of underrepresented racial and ethnic populations would be approached.
When the data indicate that the product may work differently in the population based on racial and ethnic factors, the plan should specify study design features that will support analyzes to inform the safety and efficacy of the product in racial and ethnic populations concerned.
Defined enrollment goals. Sponsors should set enrollment targets for racially and ethnically underrepresented participants based on disease epidemiology and a priori information that may impact the results of racial and ethnic groups. The authors note that, in some cases, more than proportional recruitment of certain populations may be required to investigate potential large differences.
Specific enrollment and retention strategies. The plan should detail the action plan and specific strategies for recruiting and retaining diverse participants throughout the trial, including site selection and access considerations, community engagement efforts, and plans for reduce access charges due to the design and conduct of the study.
Status of achieving enrollment goals. As the plan is updated and the study progresses, the sponsors will also discuss the status of enrollment goals with the FDA. If listing targets are not met, sponsors can be expected to discuss a plan and rationale for collecting relevant data in the post-marketing setting.
The plan should also describe the sponsor’s proposed approach to collecting data to explore potential differences in drug safety and effectiveness associated with racial and ethnic origins throughout the product’s life cycle, and plans for pediatric studies that include racially and ethnically diverse populations as part of the medical product development program.
While the guidance document targets enrollment of underrepresented ethnic and racial groups, the authors also encourage sponsors to create plans to ensure adequate enrollment of other relevant and underrepresented populations defined by demographics ( for example, sex, gender identity, disability, pregnancy status). It is unclear whether future guidance documents may be issued to more strongly recommend the inclusion of diversity plans for these other populations.
The FDA will consider the plan “an important part of the sponsor’s development program.” For drug sponsors, the FDA recommends that sponsors submit and discuss the plan with the FDA as soon as possible, but no later than the post-Phase 2 meeting where the sponsor seeks feedback regarding the trial(s). applicable pivots for the drug. Sponsors must also submit a formal meeting request to the FDA to discuss the plan at the time of submission. For devices, sponsors must submit the plan as part of the investigation plan included in the IDE request, or if an IDE submission is not required because the device is not significant, the plan can then be submitted to the FDA as part of a Q submission. Notably, the guidance document does not advise sponsors of studies on devices with no significant risk, which may not otherwise interact with the agency prior to marketing application, whether it is recommended to submit the plan to the FDA in a Q submission prior to initiating the trial.
Sponsors should also include the plan in the medical product marketing application along with a description of the successes and challenges in implementing it.
Once finalized, the draft guidelines will not be binding, raising questions about whether the FDA will take action against sponsors who do not submit a plan. Nonetheless, he announces to industry that the FDA intends to take a closer look at the composition of study populations throughout the clinical development program for drugs and devices. The comment period on the draft guidelines will end on June 13, 2022.
 For non-significant risk device studies, once the study is approved by the IRB, the trial is treated as having IDE approval without a formal submission to the FDA. Only studies on devices with significant risk require prior approval of an FDI application by the agency.